Clinical and experimental studies have demonstrated a differential response of metastases to chemotherapeutic agents depending upon the location of the metastases. The major objective of this proposal is to determine whether the response of metastatic tumor cells to chemotherapeutic agents is influenced by characteristics inherent to tumor cells, to host (organ site) factors, or to both. With the development of cloning of tumors, a novel approach may be used to differentiate these mechanisms. The hypothesis is that if the tumor cell determines chemosensitivity, clones of differeing chemosensitivity will exhibit variable responses to cytotoxic agents at the same site. Furthermore, accounting for differences in drug distribution and penetration, the same clone will exhibit similar responses to cytotoxic agents at different sites. Conversely, if host (organ site) factors are more important in determining chemosensitivity, the same clones will demonstrate different responses in different organ sites. Homogeneous clonal tumor cell populations are necessary to differentiate these different possibilities. The experimental approach will utilize clones of a mouse fibrosarcoma in both in vitro and in vivo assays. Clones demonstrating heterogeneity in response in vitro will be implanted into different host organs in vivo. By analyzing the patterns of response in different organ sites, the roles of the host and the tumor cell with regard to chemoresistance will be determined. Further understanding of the roles of the host and tumor cell in regulating chemosensitivity could help to determine whether therapy should be more specifically directed against the tumor cell or whether host functions should be enhanced.